Ramipril

6. ADVERSE REACTIONS The most common adverse reactions in patients with hypertension included headache, dizziness, fatigue, and cough ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypertension Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in ramipril patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with ramipril. The most common reasons for discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%). Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2% [n=13/651] vs. 1% [n=2/286], respectively). In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome i n the Ramipril group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of patients requiring discontinuation of treatment. Heart Failure Post-Myocardial Infarction AIRE Study: Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on ramipril are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study. Table 1. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-Controlled (AIRE) Mortality Study Adverse Event Placebo (N=982) Ramipril (N=1004) Hypotension 5% 11% Cough increased 4% 8% Dizziness 3% 4% Angina pectoris 2% 3% Nausea 1% 2% Postural hypotension 1% 2% Syncope 1% 2% Vomiting 0.5% 2% Vertigo 0.7% 2% Abnormal kidney function 0.5% 1% Diarrhea 0.4% 1% Other Adverse Reactions Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain): Body as a whole: Anaphylactoid reactions [see WARNINGS AND PRECAUTIONS ( 5.1 ) ]. Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see WARNINGS AND PRECAUTIONS ( 5.5 ) ] , syncope, and palpitations. Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia. Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. Renal: Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with a diuretic [see WARNINGS AND PRECAUTIONS ( 5.3 ) ]. Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ramipril [see WARNINGS AND PRECAUTIONS ( 5.1 ) ]. Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, and taste disturbance. Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances. Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported. Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain. 6.2 Post-Marketing Experience In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during ramipril therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown. 6.3 Clinical Laboratory Test Findings Creatinine and Blood Urea Nitrogen Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis [see WARNINGS AND PRECAUTIONS ( 5.3 ) ]. As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient's serum potassium frequently [see WARNINGS AND PRECAUTIONS ( 5.8 ) ] . Hemoglobin and Hematocrit Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit. Other (causal relationships unknown) Clinically important changes in standard laboratory tests were rarely associated with Ramipril administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

4. CONTRAINDICATIONS Angioedema related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema.( 4 ). Ramipril is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).

11. DESCRIPTION Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°-112°C. The CAS Registry Number is 87333-19-5. Ramipril's chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [ b ]pyrrole-2-carboxylic acid, 1-ethyl ester. Ramipril capsules USP are supplied as hard gelatin capsules for oral administration containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril. The inactive ingredients present are gelatin, meglumine, pregelatinized starch, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1. The structural formula for ramipril is: Its empirical formula is C 23 H 32 N 2 O 5 and its molecular weight is 416.5. Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group. structural formula for ramipril

2. DOSAGE AND ADMINISTRATION • Hypertension: Initial dose is 2.5 mg to 20 mg once daily. Adjust dosage according to blood pressure response after 2–4 weeks of treatment. The usual maintenance dose following titration is 2.5 mg to 20 mg daily as a single dose or equally divided doses ( 2.1 ). • Heart failure post-myocardial infarction: Starting dose of 2.5 mg twice daily. If patient becomes hypotensive at this dose, decrease dosage to 1.25 mg twice daily. Increase dose as tolerated toward a target dose of 5 mg twice daily, with dosage increases about 3 weeks apart ( 2.3 ). • Dosage adjustment: See respective sections pertaining to dosage adjustment in special situations ( 2.5 ). 2.1 Hypertension The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with ramipril alone, a diuretic can be added. 2.3 Heart Failure Post-Myocardial Infarction For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose of ramipril is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart. After the initial dose of ramipril, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of ramipril does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see WARNINGS AND PRECAUTIONS ( 5.5 ) , DRUG INTERACTIONS ( 7.1 ) ]. 2.4 General Dosing Information Generally, swallow ramipril capsules whole. The ramipril capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration. Concomitant administration of ramipril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium [see WARNINGS AND PRECAUTIONS ( 5.8 ) ] . 2.5 Dosage Adjustment Renal Impairment Establish baseline renal function in patients initiating ramipril capsules. Usual regimens of therapy with ramipril capsule may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25 % of the usual dose of ramipril capsule is expected to produce full therapeutic levels of ramiprilat [see USE IN SPECIFIC POPULATIONS ( Error! Hyperlink reference not valid.) ]. Hypertension For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg ramipril once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg. Heart Failure Post-Myocardial Infarction For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg ramipril once daily. The dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability. Volume Depletion or Renal Artery Stenosis Blood pressure decreases associated with any dose of ramipril depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.

1. INDICATIONS AND USAGE • Ramipril capsules USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. ( 1.1 ). • Ramipril capsules USP are indicated in stable patients who have demonstrated clinical signs of congestive heart failure post-myocardial infarction ( 1.3 ). 1.1 Hypertension Ramipril capsules USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. 1.3 Heart Failure Post-Myocardial Infarction Ramipril capsules USP are indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of ramipril to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure [see CLINICAL STUDIES ( 14.3 ) ].

10. OVERDOSAGE Single oral doses of ramipril in rats and mice of 10 g/kg to 11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension. Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.

7. DRUG INTERACTIONS • Diuretics: Possibility of excessive hypotension ( 7.1 ). • Lithium: Use with caution ( 7.3 ). • Gold: Nitritoid reactions have been reported ( 7.4 ). • NSAIDS use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.5 ). 7.1 Diuretics Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ramipril. The possibility of hypotensive effects with ramipril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ramipril. If this is not possible, reduce the starting dose [see DOSAGE AND ADMINISTRATION ( 2 ) ]. Ramipril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently. 7.2 Other Antihypertensive Agents Limited experience in controlled and uncontrolled trials combining ramipril with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system. The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate). In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended [see Dual Blockade of the Renin-Angiotensin-Aldosterone System ( 5.7 ) ]. 7.3 Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. 7.4 Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including ramipril. 7.5 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs. 7.6 Other Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients' state of anticoagulation.

12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ramipril alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ramipril and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see WARNINGS AND PRECAUTIONS ( 5.8 ) ]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma. Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ramipril remains to be elucidated. While the mechanism through which ramipril lowers blood pressure is believed to be primarily suppression of the reninangiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension. Although ramipril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients. 12.2 Pharmacodynamics Single doses of ramipril of 2.5 mg to 20 mg produce approximately 60% to 80% inhibition of ACE activity 4 hours after dosing with approximately 40% to 60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites. 12.3 Pharmacokinetics Absorption Following oral administration of ramipril, peak plasma concentrations (C max ) of ramipril are reached within 1 hour. The extent of absorption is at least 50% to 60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced. In a trial in which subjects received ramipril capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food. Distribution Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2 to 4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 μg/mL to10 μg/mL. Metabolism Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2 .5 mg to 20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously. After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ramipril, especially at low doses (2.5 mg), but the difference is clinically insignificant. Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2 to 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9 to 18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5 mg to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13 to 17 hours. In patients with creatinine clearance <40 mL/min/1.73 m 2 , peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3 to 4 times as large as it is in patients with normal renal function who receive similar doses. In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function. Excretion After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril. The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m 2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.

12.1 Mechanism of Action Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ramipril alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ramipril and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see WARNINGS AND PRECAUTIONS ( 5.8 ) ]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma. Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of ramipril remains to be elucidated. While the mechanism through which ramipril lowers blood pressure is believed to be primarily suppression of the reninangiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension. Although ramipril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients.

12.2 Pharmacodynamics Single doses of ramipril of 2.5 mg to 20 mg produce approximately 60% to 80% inhibition of ACE activity 4 hours after dosing with approximately 40% to 60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

12.3 Pharmacokinetics Absorption Following oral administration of ramipril, peak plasma concentrations (C max ) of ramipril are reached within 1 hour. The extent of absorption is at least 50% to 60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced. In a trial in which subjects received ramipril capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food. Distribution Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2 to 4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 μg/mL to10 μg/mL. Metabolism Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2 .5 mg to 20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously. After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ramipril, especially at low doses (2.5 mg), but the difference is clinically insignificant. Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2 to 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9 to 18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5 mg to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13 to 17 hours. In patients with creatinine clearance <40 mL/min/1.73 m 2 , peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3 to 4 times as large as it is in patients with normal renal function who receive similar doses. In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function. Excretion After oral administration of ramipril, about 60% of the parent drug and its metabolites are eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril. The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance <40 mL/min/1.73 m 2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations.

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3. DOSAGE FORMS AND STRENGTHS Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg ( 3 ) Ramipril capsules USP are supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.

Ramipril Ramipril RAMIPRIL RAMIPRILAT FD&C BLUE NO. 1 FD&C RED NO. 40 GELATIN, UNSPECIFIED MEGLUMINE STARCH, CORN TITANIUM DIOXIDE LUPIN;RAMIPRIL;5;mg Ramipril Ramipril RAMIPRIL RAMIPRILAT FD&C BLUE NO. 1 GELATIN, UNSPECIFIED MEGLUMINE STARCH, CORN TITANIUM DIOXIDE Light Blue LUPIN;RAMIPRIL;10;mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility. No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility. No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

ANDA077626

Ramipril

Ramipril

63187-073

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 63187-073-30

Boxed Warning: Fetal Toxicity 04/2012 Warnings and Precautions: Fetal Toxicity ( 5.6 ) 04/2012

17. PATIENT COUNSELING INFORMATION 17.1 Angioedema Angioedema, including laryngeal edema, can occur rarely with treatment with ACE inhibitors, especially following the first dose. Advise patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. 17.2 Neutropenia Advise patients to report promptly any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia. 17.3 Symptomatic Hypotension Inform patients that light-headedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue ramipril if syncope (fainting) occurs, and to follow up with their health care providers. Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking ramipril can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. 17.4 Pregnancy Female patients of childbearing age should be told about the consequences of exposure to ramipril during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. 17.5 Hyperkalemia Advise patients not to use salt substitutes containing potassium without consulting their physician. Manufactured for: Lupin Pharmaceuticals Inc ., Baltimore, Maryland 21202 United States. Manufactured by: Lupin Limited Goa - 403 722 INDIA. Revised: February 15, 2013 ID#: 231272 Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320

14. CLINICAL STUDIES 14.1 Hypertension Ramipril has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics as monotherapy for hypertension. It was approximately as effective as other ACE inhibitors and as atenolol. Administration of ramipril to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted [see WARNINGS AND PRECAUTIONS ( 5.5 ) ]. Use of ramipril in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone. In single-dose studies, doses of 5 mg to 20 mg of ramipril lowered blood pressure within 1 to 2 hours, with peak reductions achieved 3 to 6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4 to 12 weeks) controlled studies, once-daily doses of 2.5 mg to 10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mmHg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50 to 60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients, the antihypertensive effect with once-daily dosing is not adequately maintained. In most trials, the antihypertensive effect of ramipril increased during the first several weeks of repeated measurements. The antihypertensive effect of ramipril has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of ramipril has not resulted in a rapid increase in blood pressure. Ramipril has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. Ramipril was approximately as effective as other ACE inhibitors and as atenolol. In both Caucasians and Blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril. Ramipril was less effective in blacks than in Caucasians. The effectiveness of ramipril was not influenced by age, sex, or weight. In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged. 14.3 Heart Failure Post-Myocardial Infarction Ramipril was studied in the AIRE trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing ramipril to placebo in stable patients, 2 to 9 days after an acute myocardial infarction, who had shown clinical signs of congestive heart failure at any time after the myocardial infarction. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days. Patients randomized to ramipril treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to ramipril) of 5 mg twice daily. Patients were then followed for an average of 15 months, with the range of follow-up between 6 and 46 months. The use of ramipril was associated with a 27% reduction (p=0.002) in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of congestive heart failure-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of ramipril therapy were seen in both genders, and they were not affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on (and not on) various concomitant medications. At the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%).

8.5 Geriatric Use Of the total number of patients who received ramipril in U.S. clinical studies of ramipril, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.

8.3 Nursing Mothers Ingestion of a single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use ramipril in nursing mothers.

8.4 Pediatric Use Neonates with a history of in utero exposure to ramipril If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants. Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of ramipril.

8.1 Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ramipril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ramipril unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ramipril for hypotension, oliguria, and hyperkalemia [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ].

8. USE IN SPECIFIC POPULATIONS • Pregnancy: Discontinue drug if pregnancy is detected ( 5.6 , 8.1 ). • Nursing mothers: Ramipril use is not recommended in nursing mothers ( 8.3 ). 8.1 Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ramipril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ramipril unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ramipril for hypotension, oliguria, and hyperkalemia [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ]. 8.3 Nursing Mothers Ingestion of a single 10 mg oral dose of ramipril resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use ramipril in nursing mothers. 8.4 Pediatric Use Neonates with a history of in utero exposure to ramipril If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants. Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of ramipril. 8.5 Geriatric Use Of the total number of patients who received ramipril in U.S. clinical studies of ramipril, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out. One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients. 8.6 Renal Impairment A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of creatinine clearance: normal (>80 mL/min), mild impairment (40 to 80 mL/min), moderate impairment (15 to 40 mL/min), and severe impairment (<15 mL/min). On average, the AUC 0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the group with normal renal function. Over all, the results suggest that the starting dose of ramipril should be adjusted downward in patients with moderate-to-severe renal impairment.

16. HOW SUPPLIED/STORAGE AND HANDLING Ramipril Capsules, USP are available in 5 mg and 10 mg hard gelatin capsules. Descriptions of Ramipril Capsules USP are summarized below. Ramipril Capsules USP, 5 mg are: Size "4" capsules with red cap, imprinted with 'LUPIN' in black ink and red body imprinted with 'RAMIPRIL 5 mg' in black ink, containing white to off-white powder. NDC 63187-073-30 bottles of 30 NDC 63187-073-60 bottles of 60 NDC 63187-073-90 bottles of 90 Ramipril Capsules USP, 10 mg are: Size "4" capsules with light blue cap, imprinted with 'LUPIN' in black ink and light blue body imprinted with 'RAMIPRIL 10 mg' in black ink, containing white to off-white powder. NDC 63187-277-30 bottles of 30 NDC 63187-277-60 bottles of 60 NDC 63187-277-90 bottles of 90 Dispense in light-resistant, tight container with child-resistant closure. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning • When pregnancy is detected, discontinue ramipril as soon as possible ( 5.6 ). • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus ( 5.6 ). WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue ramipril as soon as possible ( 5.6 ). • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus ( 5.6 ).